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CARDIOVASCULAR JOURNAL OF AFRICA • Vol 21, No 3, May/June 2010
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Cardiovascular Topics
Erythromycin as an alternative to reduce interfering
extra-cardiac activity in myocardial perfusion imaging
MARIZA VORSTER, MM SATHEKGE, P RHEEDER
Summary
Objectives: We sought to determine whether taking oral
erythromycin prior to SPECT myocardial perfusion imaging
with Tc99m-sestamibi would reduce the amount of interfering extra-cardiac activity and improve the image quality.
Methods: A total of 96 patients who were routinely referred
for myocardial perfusion imaging were randomly assigned
to one of two groups. Patients in group A received 500 mg of
non-enterically coated erythromycin orally one hour prior to
image acquisition (45 patients). Patients in group B received
diluted lemon juice which comprises the current standard of
care in our department (51 patients). A two-day protocol was
followed and study participants received the same intervention on both days. Planar images of both the stress and rest
images were assessed visually by three experienced nuclear
medicine physicians for the presence of interfering extracardiac activity. Physicians were blinded to the detail of the
protocol and independently assessed the images.
Results: The qualitative results favoured lemon juice in
reducing the amount of interfering extra-cardiac activity.
The overall incidence of interfering extra-cardiac activity
was 46.15% in the lemon juice group vs 55.56% in the erythromycin group. However, this difference was not found to be
statistically significant (p = 0.36). The use of a MYO:EXT
ratio similar to the one described by Peace and Lloyd,11
appeared promising in quantifying interfering extra-cardiac
activity.
Conclusion: The difference between the effect of erythromycin and lemon juice on interfering extra-cardiac activity
appears statistically insignificant and erythromycin could
therefore be considered as a suitable alternative to lemon
juice.
Department Pharmacology, Steve Biko Academic Hospital,
University of Pretoria, South Africa
MARIZA VORSTER, MB ChB, FCNP (SA), MMed (Nucl Med),
MPharm Med, [email protected]
Department of Nuclear Medicine, Steve Biko Academic
Hospital, University of Pretoria, South Africa
MARIZA VORSTER, MB ChB, FCNP (SA), MMed (Nucl Med),
MPharm Med
MM SATHEKGE, MB ChB, MMed (Nucl Med)
Department Clinical Epidemiology, Steve Biko Academic
Hospital, University of Pretoria, South Africa
P RHEEDER, MB ChB, PhD
Keywords: erythromyacin, myocardial perfusion imaging, artefacts, improving diagnostic accuracy
Submitted 16/4/09, accepted 11/9/09
Cardiovasc J Afr 2010; 21: 142–147
www.cvja.co.za
Single-photon emission computed tomography (SPECT) myocardial perfusion imaging is a means of providing functional information about the left ventricle and myocardial perfusion.
Accurate and reliable determination of left ventricular function and perfusion are important to guide therapeutic management, improve risk stratification, and provide prognostic information in the cardiac evaluation of patients. Hence it is of
great importance that the results are reliable and reproducible.
However, artifacts related to abdominal activity frequently affect
the accuracy. This is due to the fact that the two most commonly
used radiopharmaceuticals: Tc99m methoxy isobutyl isonitrile
(sestamibi) and Tc-99m tetrofosmin are both excreted by the
hepatobilliary system.1,2
Due to the fact that the heart lies on the diaphragm just above
the left lobe of the liver and in the vicinity of the bowel, attenuation and scattered radioactivity from these organs can interfere
with both visual and quantitative interpretation and cause artifacts during reconstruction of SPECT images, especially in the
inferior and infero-septal walls of the left ventricle. This is most
commonly associated with rest or pharmacological stress studies
in which the hepatic uptake is most marked, and it is also seen
more frequently in women.3
Since the introduction of sestamibi, it has been recommended
that a fatty meal be given to reduce interference from liver and
gall bladder activity.4 The recent procedure guidelines adopted
by the British Cardiac Society, however, state that the value of
a fatty meal is uncertain and may be counter-productive if there
is gastro–duodenal reflux, or if the tracer reaches the transverse
colon.5
Various proposals have been made to reduce extra-cardiac
activity and its unwanted effects, with mixed results. Some of
these include prone imaging, pixel truncation, ECG-gated acquisition and supplemental exercise with pharmacological stress.1,5,6
Pharmacological interventions have included the use of cholecystokinin and metoclopramide. Recently, the effect of lemon
juice has also been evaluated.7-9 The latter comprises the current
protocol in our department.
To our knowledge, erythromycin has not been used in a
study to evaluate the effect on interfering extra-cardiac activity.
The rationale behind the use of erythromycin is the following.
Erythromycin has been shown to increase gastric emptying,
possibly by mimicking the effect of motilin after binding to the
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antral and duodenal motilin receptors. This leads to strong phase
3 contractions of the interdigestive motor complex.7 In addition,
some studies have suggested that erythromycin stimulates gall
bladder motility.10
In our study, we sought to determine whether taking oral
erythromycin prior to SPECT myocardial perfusion imaging
with Tc99m-sestamibi would reduce the amount of interfering
extra-cardiac activity and improve image quality and patient
management. An additional aim was to validate the recently
described method to quantify the level of interfering extracardiac activity – the MYO:EXT ratio.11
Methods
Study participants were patients who were routinely referred
for myocardial perfusion imaging for known or suspected coronary artery disease at the Nuclear Medicine Department of the
Steve Biko Academic Hospital (formerly known as the Pretoria
Academic Hospital). Patients were evaluated for possible exclusion criteria, after which written consent was obtained from all
study participants. See Table 1 for inclusion and exclusion criteria. A list of possible interactions with erythromycin was made
available to all study participants (Table 2).
The study commenced following ethics approval and 101
patients were enrolled in the study between 19 May and 22
September 2008. Four patients were excluded from the study due
to incomplete data and one was unable to complete the study due
to severe nausea and hypotension (Fig. 1). Clinical characteristics of patients in both groups are listed in Table 3.
Both the allocation of patients as well as the administration
of the interventions was administered by the nursing staff of
the department. All physicians were blinded to the detail of the
protocol. Patient preparation consisted of the following: at least
a four-hour fast prior to stress testing (usually overnight), no
caffeine for at least 24 hours and discontinuation of β-blockers,
calcium channel blockers, nitrates and any other drugs considered necessary. Patients were verbally checked for abstinence
from these substances prior to the study.
Patients who were allocated to group A received 500 mg of
non-enterically coated erythromycin orally one hour prior to
image acquisition.7,12 Where such patients required aminophylline, the dose was reduced to 75 mg intravenously (IV) (erythromycin metabolite increases the plasma level of aminophylline by
35%).13 Patients allocated to group B received 250 ml of diluted
lemon juice (150 ml lemon juice + 100 ml water) 10 min after
tracer injection, which is the standard of care in our department
(as validated by Cherng et al.9) Fig. 2 shows the randomisation
process.
A two-day protocol was performed with IV injection of 555
MBq of Tc99m-sestamibi on both days and study participants
underwent mostly pharmacological stress testing (0.56 mg/kg
dipyridamole IV) combined with low-level exercise. Stress images were acquired 30 min after tracer injection and rest images
between 45 and 60 min following tracer injection.
Image acquisition and processing
Patients were imaged supine using a double-headed Siemens
E-CAM gamma camera with both detectors configured at 90˚
101 patients
fulfilled criteria
TABLE 1. INCLUSION AND EXCLUSION CRITERIA
Inclusion criteria
•• Patients who were routinely
referred for myocardial perfusion imaging for known or
suspected coronary artery
disease at the Nuclear Medicine department of the Steve
Biko Academic Hospital.
(Previously known as the
Pretoria Academic Hospital.
Exclusion criteria
•• Pregnancy
•• Patients younger than 18 years
of age
•• Known hypersentivity to
erythromycin
•• Patients using gastric motility
agents which could potentially cause the gallbladder to
contract
•• Previous billiary or gastrointestinal surgery
•• Hepatic impairment
•• Significant history of upper
gastro-intestinal complaints
•• Patients using essential medication with known erythromycin interactions.
TABLE 2. POSSIBLE DRUG INTERACTIONS
WITH ERYTHROMYCIN
••
••
••
••
••
••
••
••
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CARDIOVASCULAR JOURNAL OF AFRICA • Vol 21, No 3, May/June 2010
Digoxin
Sildenafil
Dispoyramide
Warfarin
Theophylline
Alprazolam or triazolam
Ergotamine
Carbamaepine
••
••
••
••
••
••
••
••
Tacrolimus
Cyclosporine
Lovastatin or simvastatin
Bromocriptine
Cilostazol
Quinidine
Vinblastine
Other antibiotics
4 patients with incomplete
data (3 E, 1 L)
1 patient with poor clinical
condition (E)
Erythromycin
(45 patients)
Lemon juice
(51 patients)
Fig. 1. Study protocol.
TABLE 3. CLINICAL CHARACTERISTICS OF
PATIENTS IN EACH GROUP
Erythromycin Lemon juice
(n = 45)
(n = 51)
Age (mean)
59.04
58.10
Gender (male/female)
33/12
35/16
Caucasian
34
35
Black
6
9
Indian
5
4
Coloured
0
3
Co-morbidities
Acute coronary syndrome
40
45
Systemic hypertension
36
40
Diabetes mellitus
10
12
Dyslipidaemia
31
19
CVS failure
10
7
p-value
0.631
0.738
0.345
0.849
0.984
0.833
0.006
0.300
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CARDIOVASCULAR JOURNAL OF AFRICA • Vol 21, No 3, May/June 2010
and fitted with low-energy, high-resolution collimators. Gated
SPECT imaging was performed using eight frames. Thirty
projection images, each of 25 seconds’ duration, were acquired
on a 64 × 64 matrix over a 90˚ counter-clockwise rotation with a
starting angle of 45˚ (step-and-shoot mode). A zoom of 1.45 was
applied resulting in a pixel size of 1.6 mm. A Butterworth filter
was applied (order 5, cut-off 0.4) and filtered back projection
was used for reconstruction. In addition, a static LAO and LPO
view was acquired for all patients for both the stress and rest
studies for 500-K counts (Fig. 3)
Statistical analysis
Sample size was determined based on similar studies published
recently. Pearson’s Chi-squared test was used to determine
whether the baseline characteristics of the two groups were
comparable. With the exception of dyslipidaemia, no statistically
significant differences were found. A two-sample t-test with
equal variances was used to determine the correlation between
observer evaluation and the MYO:EXT ratio. In addition, the
kappa statistic was calculated (using STATA 10) to evaluate
inter-observer agreement for more than two observers with two
possible outcomes (yes/no). A p-value of less than 0.05 was
considered statistically significant in all calculations.
Data analysis
Three experienced nuclear medicine physicians evaluated static
images (LAO and LPO views) of both the stress and rest studies
of all study participants for the presence or absence of interfering
extra-cardiac activity. Observers evaluated the images independErythromycin (90 studies)
Lemon juice (102 studies)
Group A
Group B
45
Rest
45
Stress
1
exercise
44
Persantin
51
Rest
51
Stress
1
exercise
1
Dobutrex
49
Persantin
Fig. 2. Randomisation process.
%
ently of one another and were blinded to the clinical information
as well as the protocol details.
The raw anterior data for both parts of each study were
selected and regions of interest (ROIs) were created as follows: a
circular semi-automatic ROI surrounding the myocardium of the
left ventricle and an irregular, manually drawn area starting from
the infero-lateral aspect of the myocardial ROI to the medial
aspect thereof (Fig. 4). ROIs were copied between stress and rest
studies of individual patients to increase reproducibility.
The mean counts per pixel were obtained for both ROIs and
were used to calculate the ratio between myocardial activity
(MYO) and extra-cardiac activity (EXT) for each patient in a
manner similar to the one described by Peace and Lloyd.11 The
aim was to validate the use of the MYO:EXT ratio in quantification of interfering extra-cardiac activity in our patient population.
Results
The patient characteristics (Table 3) did not demonstrate any
statistically significant differences between the two study groups
in terms of demographics or co-morbidity (p > 0.05) with the
exception of dyslipidaemia, which was more prevalent in the
erythromycin group
All three physicians determined that the frequency of interfering extra-cardiac activity was higher in the erythromycin study
group when compared with the lemon juice group. Differences
between the two groups varied between 6 and 10% among the
various observers. Interference was consistently judged to be
TABLE 4. QUANTITATIVE RESULTS
Interfering extra-cardiac activity
Observer 1
Stress/rest
Observer 2
Stress/rest
Observer 3
Stress/rest
Erythromycin
42/90
(46.67%)
21/21
51/90
(56.67%)
28/23
55/90
(61.11%)
29/26
Lemon juice
38/102
(37.25%)
21/17
50/102
(49.02%)
28/22
57/102
(55.88%)
29/28
Static myocardiac stress 2008/05/19
%
66
0
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LAO 499K Duration: 80sec 256 x 256 Pix: 1.6mm 99mm Technetium
66
0
LPO 502K Duration: 80sec 256 x 256 Pix: 1.6mm 99mm Technetium
Fig. 3. Static LAO and LPO view for all patients for both the stress and rest studies for 500-K counts.
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CARDIOVASCULAR JOURNAL OF AFRICA • Vol 21, No 3, May/June 2010
70%
60%
50%
40%
30%
Fig. 4. Circular semi-automatic ROI surrounding the
myocardium of the left ventricle and an irregular, manually drawn area starting from the infero-lateral aspect of
the myocardial ROI to the medial aspect thereof.
20%
10%
TABLE 5. RESULTS OF STRESS AND REST
STUDIES SEPARATELY
Stress
Y
N
57/96
39/96
1.12
1.22
0.26
0.22
0.057
Rest
Y
N
48/96
48/96
1.08
1.24
0.21
0.19
0.0002
Number
Myo:Ext
± SD
p-value (difference
between Y and N)
95% CI
1.05-1.19 1.14-1.29 1.02-1.14 1.18-1.29
Myo:Ext = myocardium-to-extra-cardiac activity ratio; Y = presence
of interfering extra-cardiac activity; N = absence of interfering extracardiac activity; CI = confidence interval.
higher on the stress studies when compared to the rest studies
(Fig. 5, Table 4).
For the purpose of validating the MYO:EXT ratio, the
absence or presence of interfering activity was considered to
be present when at least two or three physicians concurred. The
kappa statistic revealed fair to moderate inter-observer agreement, with better agreement noted on the rest studies (κ = 0.42)
when compared to the stress studies (κ = 0.37). These values
were calculated independently of the intervention that was used.
The presence of interfering extra-cardiac activity was consistently judged higher in the erythromycin group (55.56%) when
compared to the lemon juice group (46.15%) (p = 0.36). A
strong and statistically significant relationship was found with
the qualitative evaluation when using the rest MYO:EXT (p =
0.0002). Using the MYO:EXT ratio generated from the stress
images did not yield a statistically significant result (p = 0.0568).
Table 5 combines the results of all three observers and evaluates
the stress and rest studies separately. The presence or absence of
interfering activity was considered to be positive when at least
two or three physicians concurred.
A sub-group of 48 patients was selected from the study participants in whom an additional MYO:EXT ratio was calculated on
the lateral images of both the stress and rest images. An average
value was generated for each of the 48 patients using both the
0%
Obs 1
Lemon juice
Obs 2
Obs 3
Erythromycin
Fig. 5. Comparison of results from the two studies.
anterior and lateral images. This was calculated separately for
stress and rest studies and correlated with the qualitative results.
The results were similar to those provided in the table above
with only the ratios obtained from the rest images proving to be
statistically significant (p = 0.0002).
Discussion
SPECT myocardial perfusion imaging with sestamibi is a widely
used, non-invasive diagnostic method for assessing patients with
coronary artery disease with regard to severity, extent, prognosis
and therapeutic response. The initial myocardial uptake of sestamibi is related to regional myocardial blood flow and is dependent on a mitochondrial-derived membrane electrochemical gradient. Sestamibi is predominantly excreted by the hepatobilliary
system. Unfortunately, this mechanism of excretion is frequently
the source of artifacts due to abdominal activity, which affects
both observer interpretation and reconstruction. Various proposals have been made to overcome this problem in order to improve
diagnostic accuracy.
Recently, a prospective, randomised trial with 86 patients and
82 controls was conducted to evaluate the use of metoclopramide. This study followed two previous studies with conflicting
results. Therefore the aim was to conclusively determine whether
metoclopramide was useful in reducing artifacts related to
abdominal activity in myocardial perfusion SPECT. In this study
metoclopramide showed neither a qualitative nor quantitative
impact on abdominal activity in myocardial perfusion imaging.8
The use of metoclopramide is based on the rationale that it
is a prokinetic drug, which should enhance gastric clearance of
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CARDIOVASCULAR JOURNAL OF AFRICA • Vol 21, No 3, May/June 2010
Tc99m MIBI. However, a recent study failed to demonstrate any
effect of metoclopramide on interfering extra-cardiac activity.
A study done recently by Cherng et al.9 concluded that diluted
lemon juice accelerated the transit of tetrofosmin through the
liver parenchyma, leading to improved image quality on myocardial perfusion SPECT images. Prior to this, various studies had
been done in order to evaluate the effects of water, milk, milkshakes, and fatty meals on imaging time.11 The rationale behind
these protocols is the following:
•• Clearance of activity located in the gall bladder and hepatic
duct into the duodenum and bowel may be stimulated by fatty
meals, milkshakes and intravenous cholecystokinin.
•• Water and sandwiches have been used to fill the stomach and
push the bowel away from the myocardium, thus exerting a
volume effect. In addition, peristaltic gastric motility may
be stimulated by oral consumption following pre-injection
fasting, and the upper gastro-intestinal tract activity may
therefore be diluted.6
A study by Peace and Lloyd11 evaluated the effect of imaging
time, the radiopharmaceutical used, and full-fat milk or water on
interfering extra-cardiac activity in myocardial SPECT in 260
patient acquisitions. The following conclusions were made from
this study:
•• The quantitative results indicated that oral administration of
full-fat milk or water made no significant difference to extracardiac activity.
•• There was no significant difference between tetrofosmin and
sestamibi at any point.
•• Delayed imaging significantly reduced extra-cardiac activity
interfering with observer interpretation.
•• More importantly, however, was the development of a method
to quantify the myocardial-to-extra-cardiac activity ratio,
which correlated significantly with observer interpretation of
myocardial perfusion studies.11
Other studies performed
Boz et al.4 investigated the volume effect of the stomach in
patients undergoing a same-day exercise–rest protocol. After
the rest study, patients were given either 200 ml of water and
a sandwich or were fasted and imaged again within 30 mins.
Quantitative and observer analysis showed significantly reduced
activity inferior to the left ventricle in the meal group due to an
expanded stomach.4
Hurwitz et al.6 studied the effect of a milkshake taken either
immediately after injection or just before imaging. An early
drink decreased gallbladder activity, but had no effect on the liver
parenchyma at 15 and 110 min. Patients drinking a milkshake
just prior to imaging showed a prompt 26% reduction of activity
inferior to the myocardium.6
Van Dongen and van Rijk qualitatively investigated the effects
of administering 450 ml of water 10 mins before imaging and/
or 150 ml of whole milk 10 mins after injection. Visual analysis
showed significantly fewer patients with interfering activity
when a milk-only protocol was used, compared with water only
or no drink, for images reconstructed by FBP. A combined milkand-water protocol showed the least number of studies with
interfering activity, compared with water-only and milk-only
protocols.1
Most recently, Hara et al.3 reported on the use of soda water
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(given in the form of a carbonated soft drink) in conjunction
with adenosine stress myocardial perfusion imaging and in
the Monzen position. (This is a body-positioning manoeuvre
to increase the distance between the heart and the intestine by
raising the left arm and curving the trunk slightly to the right.)
According to their report, a carbonated beverage distended the
stomach with gas and lessened artifacts from intestinal radiotracer activity. Additional benefits included the faster clearance
of gas and a smaller amount of fluid needed to distend the stomach, which is especially desirable in patients with left ventricular
dysfunction.3
Interfering extra-cardiac activity therefore remains a significant problem and a limitation to accurate interpretation of
myocardial perfusion imaging. In our study, interfering extracardiac activity was present overall in 54% of the stress images
and 48% of the rest images, when the results were combined
from all three observers for both groups. Almost all the stress
studies were performed with Persantin, confirming once again
the higher incidence of interfering activity on pharmacological
stress studies.
In our Nuclear Medicine Department, the use of diluted lemon
juice has replaced the former protocol of bread and milk. Lemon
juice was perceived to reduce the amount of interfering activity
significantly, although the effects of the two protocols were never
formally compared. When evaluating the qualitative results of
this study, lemon juice appeared to be superior in reducing the
amount of interfering activity, with all three observers reporting
less interference in the lemon juice group. However, this was not
found to be statistically significant. The superiority of lemon
juice in this setting might be explained solely on the basis of a
much larger volume of fluid consumed, which might have led to
stomach distension.
Limitations of this study
The experimental design was sub-optimal, with individuals
being exposed to the same intervention during both parts of the
study (stress and rest). A better design might have been to expose
individuals to both interventions on different days. However, the
inherent differences in interfering activity on stress and rest studies (even in the absence of any intervention) present a diagnostic
dilemma.
A third and even a fourth comparison group would have been
helpful in validating the results with one group serving as a
control (receiving no intervention) and the other receiving milk
and bread (according to our previous protocol). However, considering the decrease in the amount of interfering activity perceived
with the use of lemon juice, the addition of the latter two groups
were considered to be unethical.
Upon final statistical analysis, the study appeared to be slightly underpowered, which could have resulted in a type II error.
There were suspected errors during the randomisation process,
which might have resulted in the higher incidence of dyslipidaemia in the erythromycin group. The calculation method of the
MYO:EXT ratio as described by Peace and Lloyd11 could not be
replicated exactly due to differences in acquisition parameters as
well as the software used for image processing.
Despite the above limitations, the use of diluted lemon juice
appeared to be beneficial in reducing interfering extra-cardiac
activity in MPI studies where sestamibi was used. Furthermore,
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CARDIOVASCULAR JOURNAL OF AFRICA • Vol 21, No 3, May/June 2010
erythromycin should be considered as an alternative to lemon
juice where patients find it more acceptable and in particular
when taking into account the low cost and the low incidence of
adverse effects.
Our secondary aim was to validate the method as described
by Peace and Lloyd11 to quantify the amount of interfering extracardiac activity (MYO:EXT). A Xeleris workstation was used to
select the raw anterior projection data and to create ROIs in a
manner similar to the one described. The mean MYO:EXT value
calculated in stress studies with interference was 1.12 compared
to a value of 1.22 in stress studies without interference. Although
these values correlated with the qualitative evaluation, in that
scans without interference resulted in a higher value, the difference between these values was not statistically significant (p =
0.057).
The mean value determined on the rest images with interference was 1.08 and without interference it was 1.24. Here, a
strong and statistically significant relationship was determined
(p = 0.0002). These results suggest that the use of the MYO:EXT
in quantifying the amount of interfering extra-cardiac activity
might be valuable. However, it seems likely that further confirmatory studies will be needed and that the quest for the reduction
of interfering extra-cardiac activity continues.
Conclusion
The difference between the effect of erythromycin and lemon
juice on interfering extra-cardiac activity appears statistically
insignificant (p = 0.36), and taking into account the better
acceptability of erythromycin, this could be considered a suitable alternative to lemon juice. Furthermore, the use of the
MYO:EXT ratio seems promising in our setting.
The authors thank Sr Cecilia Corbett and the rest of the nursing staff and radiographers at the Nuclear Medicine Department of the Steve Biko Academic
Hospital for the practical implementation of this study. Special thanks also
go to the following physicians who interpreted the data: Drs P Mpikashe, N
Soni, W Jansen van Vuuren, NE Nyakale and NP Mokgoro.
147
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